2. Academic Validation
  3. Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives

Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives

  • Bioorg Med Chem Lett. 2008 Mar 15;18(6):2114-21. doi: 10.1016/j.bmcl.2008.01.093.
Michael J Costanzo 1,  Stephen C Yabut,  Han-Cheng Zhang,  Kimberley B White,  Lawrence de Garavilla,  Yuanping Wang,  Lisa K Minor,  Brett A Tounge,  Alexander N Barnakov,  Frank Lewandowski,  Cynthia Milligan,  John C Spurlino,  William M Abraham,  Victoria Boswell-Smith,  Clive P Page,  Bruce E Maryanoff
Affiliations

Affiliation

  • 1 Research and Early Development, Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477-0776, USA. mcostanz@prdus.jnj.com
PMID: 18272363 DOI: 10.1016/j.bmcl.2008.01.093
Abstract

We have explored a series of spirocyclic piperidine amide derivatives (5) as tryptase inhibitors. Thus, 4 (JNJ-27390467) was identified as a potent, selective tryptase inhibitor with oral efficacy in two animal models of airway inflammation (sheep and guinea pig asthma models). An X-ray co-crystal structure of 4 x tryptase revealed a hydrophobic pocket in the enzyme's active site, which is induced by the phenylethynyl group and is comprised of amino acid residues from two different monomers of the tetrameric protein.

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